1. Field of the Invention
The present invention relates to a stabilized pharmaceutical composition of (R)-2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4- spiro-3'-pyrrolidine-1,2',3,5'-tetrone (hereinafter, referred to as "AS-3201") having a potent aldose reductase inhibitory activity.
2. Description of Related Art
AS-3201 is the compound of the following formula. Said compound is described in Example 22 of Japanese Patent No. 2516147 (U.S. Pat. No. 5,258,382), Reference Example 12 of JP-A-6-192222 (Chem. Abstr., 122, 9860 (1995)), and Experiment of JP-A-8-176105 (Chem. Abstr., 125, 221569 (1996)), and its potent aldose reductase inhibitory activities are disclosed therein. ##STR1##
Example 28 of Japanese Patent No. 2516147 (U.S. Pat. No. 5,258,382) describes a method for preparing specific tablets of AS-3201. That is, it is described therein that AS-3201 (1 g), corn starch (25 g), lactose (58 g), crystalline cellulose (11 g), hydroxypropylcellulose (3 g), light anhydrous silicic acid (1 g) and magnesium stearate (1 g) are blended, granulated and made into 1,000 tablets each weighing 100 mg by a conventional method.
During the studies on methods for preparing AS-3201-containing pharmaceutical compositions having a good stability on store, the present inventors have found that AS-3201 drug substance per se is stable against heat and humidity, but when AS-3201 is mixed with pharmaceutical excipients or carriers, AS-3201 shows a tendency of increasing its degradation product at a higher temperature under higher humidity.
Under such circumstances, the present inventors have further intensively studied, and have found that the stability of AS-3201-containing pharmaceutical compositions is remarkably improved by adding thereto as a stabilizer at least one acidic substance having an acidity more potent than that of AS-3201, and finally have accomplished the present invention.